Niemann-Pick C1 Disease Gene: Homology to Mediators of Cholesterol Homeostasis

• Published in: Science (American Association for the Advancement of Science) 1997-07, Vol.277 (5323), p.228-231
• Main Authors: Carstea, Eugene D., Morris, Jill A., Coleman, Katherine G., Loftus, Stacie K., Zhang, Dana, Cummings, Christiano, Gu, Jessie, Rosenfeld, Melissa A., Pavan, William J., Krizman, David B., Nagle, James, Polymeropoulos, Mihail H., Sturley, Stephen L., Ioannou, Yiannis A., Higgins, Maureen E., Comly, Marcella, Cooney, Adele, Brown, Anthony, Kaneski, Christine R., Blanchette-Mackie, E. Joan, Dwyer, Nancy K., Neufeld, Edward B., Chang, Ta-Yuan, Liscum, Laura, Strauss, Jerome F., Ohno, Kousaku, Zeigler, Marsha, Carmi, Rivka, Sokol, Jacob, Markie, David, O'Neill, Raymond R., van Diggelen, O. P., Elleder, Milan, Patterson, Marc C., Brady, Roscoe O., Vanier, Marie T., Pentchev, Peter G., Tagle, Danilo A.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino acids; Anatomy; Biological and medical sciences; Carrier Proteins; Cholesterol; Cholesterol - metabolism; Cholesterol, LDL - metabolism; Cholesterols; Chromosome Mapping; Chromosomes, Human, Pair 18; Cloning, Molecular; Codons; Complementary DNA; DNA; Drosophila Proteins; Errors of metabolism; Exons; Genetic aspects; Genetic Disorders; Genetic mutation; Genetics; Homeostasis; Humans; Hydroxymethylglutaryl CoA Reductases - chemistry; Inborn errors of metabolism; Insect Proteins - chemistry; Intracellular Signaling Peptides and Proteins; Lipids (lysosomal enzyme disorders, storage diseases); Literary Devices; Lysosomes - metabolism; Medical disorders; Medical research; Medical sciences; Membrane Glycoproteins; Membrane Proteins - chemistry; Metabolic diseases; Metabolism, Inborn errors of; Molecular Sequence Data; Mutation; Nervous system diseases; Niemann Pick diseases; Niemann-Pick Diseases - genetics; Niemann-Pick Diseases - metabolism; Open reading frames; Patients; Polymorphism, Single-Stranded Conformational; Proteins - chemistry; Proteins - genetics; Proteins - physiology; Receptors, Cell Surface - chemistry; Scientific Concepts; Sequence Homology, Amino Acid; Storage; Transfection
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.277.5323.228

Niemann-Pick type C (NP-C) disease, a fatal neurovisceral disorder, is characterized by lysosomal accumulation of low density lipoprotein (LDL)-derived cholesterol. By positional cloning methods, a gene (NPC1) with insertion, deletion, and missense mutations has been identified in NP-C patients. Transfection of NP-C fibroblasts with wild-type NPC1 cDNA resulted in correction of their excessive lysosomal storage of LDL cholesterol, thereby defining the critical role of NPC1 in regulation of intracellular cholesterol trafficking. The 1278-amino acid NPC1 protein has sequence similarity to the morphogen receptor PATCHED and the putative sterol-sensing regions of SREBP cleavage-activating protein (SCAP) and 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase.